New Diagnostic approaches and Antimicrobial Management of Infectious Diseases: An Overview from Kuwait

Transcription

1 New Diagnostic approaches and Antimicrobial Management of Infectious Diseases: An Overview from Kuwait Eiman Mokaddas MD, FRCPath Professor of Clinical Microbiology Faculty of Medicine Kuwait University

2 Outline Introduction Antimicrobial usage in the 21st Century Need for new diagnostic approaches What infections are priorities for such approaches?? Sepsis Pneumonia Impact on antimicrobial management of ID Overview from Kuwait

3 Introduction

4 New Diagnostic approaches and Antimicrobial Management of Infectious Diseases: An Overview from Kuwait Eiman Mokaddas MD, FRCPath Professor of Clinical Microbiology Faculty of Medicine Kuwait University

5 Definition of New Antibiotics New Antibiotic: Anything that we introduce to bacteria and going to see resistance to!

6 Antibiotic therapy if indiscriminately used may turn out to be medical flood that temporarily cleans and heals but ultimately destroys life itself Felix Marti-Ibanez, 1955

7 Total no. of new antimicrobials As Antibiotic Options Decline IDSA. Clin Infect Dis 2009;48:1

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9 nine

10 Defining ESKAPE? Highlighting troublesome bacteria with the ability to escape the effects of current antimicrobial agents E Enterococcus faecium S Staphylococcus aureus C Clostridium difficile A Acinetobacter baumannii P Pseudomonas aeruginosa E Enterobacteriaceae Peterson Peterson LR. Clin LR. Infect Clin Infect Dis. 2009;49:992 Dis. 2009;49:992

11 IDSA. Clin Infect Dis 2010;50:1081

12 THE ANTIMICROBIAL RESISTANCE CHALLENGES OF THE

13 Hit hard Hit fast Paul Ehrlich Get it right first time If and when antibiotics are indicated, the philosophy is now based on attempting to

14 Does Inappropriate antimicroboial therapy result in antibiotics resistance??? OR Antibiotic resistance leads to inappropriate therapy??? 12/23/2013 E Mokaddas MD

15 VICIOUS CYCLE??? 12/23/2013 Mokaddas E, MD

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17 What could be the actions today???

18 Antimicrobial Stewardship The process of appropriate usage of antimicrobial agents aiming at prevention of antimicrobial resistance

19 Education Rational use of antibiotics Proper Laboratory Diagnosis Infection Control De-escalation Vaccination

20 1. Role of new and rapid diagnostic tools in the early diagnosis of sepsis

21 SEPSIS = Infection + Systemic inflammation E.Mokaddas, MD 12/23/2013

22 Sepsis Worldwide: 30,000,000 cases / year USA: / year Martin GS et al. N Engl J Med 2003;348: Angus DC et al. Crit Care Med 2001; 29: Germany: ~ / year Rychlik R et al. Gesundh Ökon Qual Manag 2000; 5: /23/2013 E.Mokaddas, MD

23 Mortality rate increases with increasing severity Mortality rate is: Down scale in no time 7% in patients with SIRS 16% in patients with Sepsis 20% in patients with Severe Sepsis 46% in patients with Septic Shock Rangel-Frausto et al. (JAMA 1995) 12/23/2013 E.Mokaddas, MD

24 The Golden Hour And The Silver Day 12/23/2013 Footer Text 24

25 We ought to spend more time to search for an accurate diagnosis rather than search for the Magic Bullet for the treatment of Sepsis" Roger Bone, 1996 E.Mokaddas, MD 12/23/2013

26 Prompt Diagnosis of Sepsis: Unachievable goal 12/23/2013 E.Mokaddas, MD

27 Experience from Kuwait

28 A. Molecular diagnosis of sepsis

29 Conventional culture system 1. < 50% positive 2. TAT hrs

30 Evaluation of the comperative performance of Verigine Blood Culture Nucliec acid System to Conventional Techniques in a Tertiary-care Hospital in Kuwait *Mokaddas EM 1, 2, Behbehani A 2, Abdullah A 2, Shatti S 2. 1 Microbiology Department, Faculty of Medicine, Kuwait University, Kuwait. 2 Laboratory Department, Ibn Sina Hospital, Kuwait

31 The diagnosis of bacteremia and sepsis is a priority in a Clinical Microbiology Department as they carry high mortality ( 20-50%). Early correct antibiotic treatment is correlated with higher survival rates. This is the main reason why broad spectrum antibiotics are usually administered until the microbiology results are known.

32 Once the bacterial pathogen is known, treatment can be adjusted to a more specific antibiotioc therapy. A key predictor of mortality rates in patients with severe blood stream infection is the time to identification of the causative pathogen and initiation of targeted therapy.

33 Rapid Diagnosis Rapid identification And of blood isolates is important Antimicrobial in patient stewardship management as well as antimicrobial stewardship.

34 The Verigene Gram-positive and Gram negative Blood Culture (BC-GP, BC-GN)) system (Nanosphere, USA) is a qualitative multiplexed automated nucleic acid in vitro diagnostic test for the direct identification of Grampositive With and a Gram TAT negative of 2 hrsbacteria and their genetic resistance markers.

35 Verigene BC-GP and BC-GN identifiable targets 12/23/ Footer Text

36 NB. Of the staphylococci only S.aures, S. epidermidis and S. lugdumesis can be identified as the other staphylococci are not present in the data base.

37 Targets Bacterial Targets Resistance Marker Organism/Gene Acinetobacter spp. Citrobacter spp. Enterobacter spp. Proteus spp. E. coli Klebsiella pneumoniae Klebsiella oxytoca Pseudomonas aerogenes Serratia marcescens CTX-M VIM KPC IMP NDM OXA (48/23/40/58) N.B. Stenotrophomonas maltophilia cannot be identified as it is not present in the data base

38 Objectives To evaluate the performance of Verigene ( BC-GP and BC-GN) nucleic acid test for the direct identification of Gram-positive and Gram-negative bacteria from positive blood culture bottles in comparison with Gene Xpert system (Cephide, USA) for Gram-positive bacteria and with the conventional culture technique for both Gram-positive and Gram-negative bacteria. To evaluate the performance of Verigene ( BC-GP) and ( BC- GN) for the detection of resistant markers directly from positive blood culture bottles in comparison with conventional culture technique. To evaluate the impact of rapid detection of the causative pathogens from blood on the management of patients

39 Materials and Methods All the demographic data including the age, sex, patient location, underlying clinical condition, clinical and laboratory data suggesting sepsis, initial empirical therapy, adjusted therapy and outcome of the patients were collected. For Gram-positive bacteria: All blood culture bottles ( Bactec, Bekton Dickinson, USA) showing Gram-positive cocci by Gram stain were processed in: Verigene for BC-GP according to the manufacturer s instructions GeneXpert ( Cepheid, USA) for BC-GP ( only for Grampositive cocci in clusters) All the positive blood culture bottles were simultaneously cultured by conventional methods for both ID as well as susceptibility using Vitek II, and Vitek MS ( Biomerioux, France)

40 Materials and Methods For Gram-negative bacteria: All blood culture bottles showing Gram-negative bacilli by Gram stain were processed in: Verigene for BC-GN according to the manufacturer s instructions All the positive blood culture bottles were simultaneously cultured by conventional methods for both ID as well as susceptibility using Vitek II, and Vitek MS A total of 11 QC strains of different streptococci were included in the evaluation

41 Results A. Gram-positive 12/23/ Footer Text

42 A total of 63 patients with positive blood culture for Gram-positive cocci were included in the evaluation 12/23/2013 Footer Text 42

43 Table 1: Comparison between results of Verigine and conventional culture for Gram-positive bacteria Gram-positive Virigine Conventional culture Staphylococcus aureus S.epidermidis S.homonis 0 1 S.hemolyticus 0 3 Other Staphylococci 9 6 Enterococcus fecalis 9 9 Enterococcus fecium 4 4 Streptococcus pneumoniae 2 2 Streptococcus mitis 1 2 Streptococcus spp. 2 1 Micrococcus spp. 1 0

44 Table 2: Comparison between results of Verigine and conventional culture for 11 QC strains Gram-positive cocci ( QC strains) Verigine Conventional % Concordance Streptococcus pneumoniae Streptococcus agalactiae Streptococcus pyogenes Enterococcus fecium

45 Table 3: Comparison between Verigine, Cephid Gene Xpert and conventional culture for Staphylococcus spp. Staphylococcus spp. Verigine Gene Xpert Conventional culture % Concordance Methicillin sensitive Staphylococcus aureus S.epidermidis S.homonis S.hemolyticus

46 Table 4: Comparison between Verigine and conventional culture for detection of reistance markers for Staphylococcus spp. Verigine Conventional Culture Methicillin sensitive staphylococcus aureus TN Mec A negative Mec A positive 11 FP 2 MRSA 2 TP 1 FN Methicillin-resistant coagulase-negative TP Staphylococci 0 15

47 Table 5: Comparison between Verigine and conventional culture for detection of reistance markers for Enterococcus spp. Conventional Culture VAN A and B negative Verigine VAN A and B positive TN Vancomycin sensitive Enterococcus fecalis 9 0 Vancomycin-sensitive Enterococcus fecium 2 0 FN Vancomycin-resistant Enterococcus fecium 2 0

48 A total of 63 patients with positive blood culture for Gram-negative cocci were included in the evaluation 3 of them were Stenotrophomonas maltophila Not detected

49 Table 6: Comparison between results of Verigine and conventional culture for Gram-negative bacteria Gram negative Verigine Conventional culture % Concordance E.coli Acinitobacter spp Klebsiella pneumoniae Pseudomonas aeruginosa Pseudomonas oryzihabitans Enterobacter spp Proteus spp Serratia marcescens

50 Table 7: Comparison between Verigine and conventional culture for detection of reistance markers for Gram-negative bacteria Bacteria (No.) Verigine Conventional culture % Concordance E.coli (24) ESBL Non-ESBL klebsiella pneumoniae (8) ESBL Non-ESBL Enterobacter spp (2) ESBL Non-ESBL Serratia marcescens (1) ESBL Non-ESBL Pseudomonas aeruginosa (7) Carbapenem resistant Non-carbapenem resistant Acinitobacter spp. (15) Carbapenem resistant Non-carbapenem resistant

51 Table 8: Impact of rapid adentification of Gram-positive bacteria on the modification of the empirical antibiotic therapy Gram positive bacteria Deescalate Escalate Continue same antibiotic Stop antibiotic Staphylococcus spp Enterococcus spp Streptococcus pneumoniae Streptococcus mitis

52 Table 9: Impact of rapid adentification of Gramnegative bacteria on the modification of the empirical antibiotic therapy Gram- negative bacteria De-escalate Escalate Continue same antibiotic Enterobacteriacae Pseudomonas aeruginosa Acinitobacter spp

53 Molecular diagnosis of sepsis TAT 2 hrs

54 B. Procalcitonin as a septic marker

55 Biomarkers for stratification of septic patients 12/23/2013 E.Mokaddas, MD

56 To achieve early and accurate detection of sepsis To differentiate infection from noninfectious SIRS To prognosticate clinical outcome 12/23/2013 E.Mokaddas, MD

57 Hospitals and particularly ICUs have a great need for markers which are specific and reliable indicators of Sepsis! 12/23/2013 E.Mokaddas, MD

58 Expectations on an innovative Clinical aspects specific Recognises only septic conditions ( no false positives) Sepsis Marker Technical aspects Applicable in lab routine Available 24/7 Sensitive Recognises all septic conditions ( no false negatives) Short time to result 12/23/2013 E.Mokaddas, MD

59 Procalcitonin PCT The Aminoacid-Sequence Procalcitonin (PCT) of Pro Phe Arg Ser Ala Leu Glu Ser Ser Pro Ala Asp Pro Ala Thr LeuSer Glu Asp Glu Ala ArgLeuLeuLeu Ala 1 Ala Ala Pro SerAsp Leu Arg Ser Ser Gly Glu Arg Glu Gln Glu Gln Ser Glu LeuGlu Ser Ala Lys Met Gln Yal Lys Arg Cys SerThr CysMet Leu Gly Thr Tyr Thr GlnAsp PheAsnLys Phe His Ala Ile Gly ThrPheProGlnThr Yal Gly Gly As Leu Ala = N-ProCT = Calcitonin = Katacalcin = Cleavage site of Endopeptidases PAM = Peptidyl-Amidating Monooxygenase 12/23/2013 E.Mokaddas, MD Asn Ala Asn Gln Pro PAM Met Ser Val His Pro Arg His Asp Arg Glu Leu As Gln Asp Tyr Leu Yal Pro Gly Lys Arg Asp Met Ser Ser Lys

60 PCT Levels increase with Extension of Infection and Severity of Disease High Range of Concentrations - Parallels to Severity of Inflammation TAT is 30 mints -0.5 ng/ml: no Sepsis ng/ml: Sepsis likely - > 2 ng/ml: High Risk of Patient: Sepsis/Sev.Sep/SS! - Stable in Blood Samples - Store at Room Temperature - Half-Life in Plasma: 25-30hrs (1 Day) - Measure 1x per Day 12/23/2013 E.Mokaddas, MD

61 IDSA October 2013 San Fransisco 12/23/ Footer Text

62 PCT Controversies!!! 12/23/ Footer Text

63 Pro-PCT 12/23/ Footer Text

64 Rapid increase Rapid decrease Over 24 hrs No increase in viral infection TAT is 30 mints Not influenced by steroidal and non-steroidal antiinflammatory sgents The increase is proportional to severity of sepsis and Sofa score Intensive care Medicine,2011, 37: /23/2013 Footer Text 64

65 Anti-PCT 12/23/ Footer Text

66 Will PCT level improve survival and reduce antibiotics exposure in ICU patients? No big difference in survival between PCT and control Lancet ID, 2013, 13: /23/2013 Footer Text 66

67 Will PCT level help to reduce antibiotic exposure?? YES PCT had 2.7 more days without antibiotic exposure Limitation of the study: 53% PCT group were not treated according to protocoal?? 12/23/2013 Lancet ID, 2013, 13:

68 Case 1 A 40 year-old male Admitted to the ICBU 35% burn on 18 th June, 2013 Severe hypotension Started on Meropenem immediately On the 23 rd June blood grew MDR Acinitobacter baumanii sensitive to colistin only Same bacteria grew in Wound, ETT 12/23/2013 Footer Text 68

69 Case Meropenem Blood culture positive Colistin Temp WBC PCT /6 20/6 21/6 23/6 24/6 25/6 26/6 27/6 29/6 30/6 4th July 11th July 12/23/2013 Footer Text 69

70 Case 2 57 year subdural hematoma MICU Sepsis: Started on Pip/Tazo ETT Blood Culture Both grew Klebsiella pneumoniae ESBL Shifted to Meropenem 12/23/2013 Footer Text 70

71 Case Meropenem Temp WBC PCT rd Aug 6th Aug 8th Aug 9th Aug 11th Aug 14th Aug 15th Aug 12/23/2013 Footer Text 71

72 Prompt modification of therapy upon increase in PCT Antimicrobial Stewardship 12/23/2013 Footer Text 72

73 2. Role of new and rapid diagnostic tools in the early diagnosis of pneumonia 12/23/

74 Pneumonia Life-threatening acute infection of LRT»incidence Germany »up to 5% of patients admitted to a hospital for other causes develop a pneumonia 2»fast progressing disease American Thoracic Society / IDSA classifies»community-acquired pneumonia (CAP)»acquired in the community without any history of medical intervention»healthcare-associated pneumonia (HCAP)»occurs in a non-hospitalized patient with extensive healthcare contact»hospital-acquired pneumonia (HAP) 1 Höffken et al, S3 Leitlinie CAP (2009) 2 Talan et al, Clin Cour, Vol 25 (2007)»occurs 48 hours or more after admission»ventilator-associated pneumonia (VAP) after endotracheal 74

75 Microbial etiology of pneumonia * CDC: Prevention of Healthcare-Associated Pneumonia, Management of mdr Organisms in Healthcare Settings, American Thoracic Society: HAP, VAP, HCAP II Guideline, CAP Guideline Paul-Ehrlich-Gesellschaft CAP-Leitlinie: Nosocomial pneumonia: prevention, diagnosis, treatment, European Respiratory Society: Lower Respiratory Tract Infections, British Society of Antimicrobial Chemotherapy:. HAP Guideline, Canadian Guideline Committee: VAP Diagnosis and Treatment. 75

76 Hospital-acquired pneumonia» caused by a wide variety of pathogens» spectrum depends on the circumstances pneumonia was acquired» polymicrobial in 25-30%, depending on subtype 1» common pathogens include aerobic gram-negative bacilli gram-positive cocci» % false-negative cultures 1» hospitalized pneumonia due to viruses / fungi significantly less common, except in immune compromised patient bacteria often drug-resistant 1 Fabregas, N Anesthelogy, Vol 4 Issue 4, (2009) 76

77 Clinical relevant resistance in It is not just MRSA.. pneumonia»ß-lactam-resistance, including ESBL»KPC-resistance»Macrolide-resistance»Quinolone-resistance»Multi-drug resistance (MDR) 77

78 Challenges in testing respiratory tract infections 12/23/

79 Reduces mortality Mortality rates reaches up to 36% Reduces length of Rapid and accurate diagnosis and effective stay initial treatment Successful knowing: outcome What is the pathogen?? Reduces resistance development Which antibiotic to use?? Which antibiotic will fail?? Reduces Cost 12/23/

80 Empirical therapy for pneumonia Inappropriate empiric therapy» empirically based initial regimen wrong in up to % of cases 1» associated with increased mortality,» adequate initial treatment significantly reduces mortality LOS costs per patient outcome benefits from faster diagnostics 3 Alvarez-Lerma F. Intensive Care Med 1996; 22: Celis R, et al. Chest 1988; 93:318 24; Kollef MH, Ward S. Chest 1998; 113: Luna CM, et al. Chest 1997; 111:676 85; Rello J, et al. Am J Respir Crit Care Med 1997; 156: Kollef et al, Chest Feb;115(2): Talan et al, Clin Cour, Vol 25 (2007) 3 Rello J et al, Am J Respir Crit Care Med 1997;156:

81 Female, 73 y CASE STUDY Empiric treatment Adjusted treatment 0 day 1 Dyspnoe Fever Chest pain Chest radiograph lung infiltrate CRB Mortality 1% CAP Hospitalization 3 Resp. insufficient Chest radiograph progressive infiltrate CRB Mod. AST Score + Mortality 30% scap ICU..14 Discharge fast molecular testing Sputum culture fluoroquinolone-resistant P. aeruginosa 1 Short inpatient hospitalization 2 Severe pneumonia 81

82 Role of faster molecular testing in making difference in the standard of care in the management of pneumonia In less than 4 hours Health economic modeling of the impact of fast pneumonia testing 12/23/

83 UNMET MEDICAL NEED ISDA; CID 2011, 52 (Suppl 4) 83

84 Evaluation of P50 Pneumonia Application in the rapid diagnosis of pneumonia in a tertiary-care hospital in Kuwait Dr. Aneesa Abdulla Dr. Shama Shatti Dr. Ahmed Behbehani Professor Eiman Mokaddas 12/23/

85 12/23/

86 12/23/

87 ANTIBIOTIC RESISTANCE MARKERS 2012 Curetis AG Application V1.0 87

88 Multiplex PCR and array-based detection 12/23/

89 Objectives To evaluate the role of in the rapid diagnosis of pneumonia ( Both CAP and HAP) and the detection of resistance markers in comparison with the conventional culture techniques To evaluate the impact of rapid molecular diagnosis of pneumonia on the management of patients 12/23/

90 Methods All patients with the clinical diagnosis of pneumonia both CAP, HAP and VAP from 3 ICU s, one Organ Transplant Department, and KCCC/ Shaikha Badria Center for Cancer and Chemotherapy admitted to the hospital from November 2012 till April 2013 were included in the evaluation. 6 patients on mechanical ventilation with no evidence of pneumonia were included as surveillance All relevant clinical data were collected Sputum, ETT s or BAL were inoculated into cartridge and processed as well by conventional culture technique 12/23/

91 Results 12/23/ Footer Text

92 A total of 45 patients were included in the evaluation VAP 18 HAP 10 CAP 11 6 surveillance cases 12/23/2013 Footer Text 92

93 OTC 17 KCCC/SB 10 IBS ICU 6 ICBU 9 IBS Wards 3 12/23/2013 Footer Text 93

94 The detailed data on all the patients: Underlying conditions Clinical diagnosis Signs of infection ( e.g. fever, WBC, PCT) Microbiology diagnostic findings by Unyvero compared to the conventional culture techniques for both ID as well as antimicrobial susceptibility testing results Empirical antibiotic therapy Modification of antibiotic therapy based on Unyvero results in 4 hrs The final outcome of the patients. 12/23/2013 Footer Text 94

95 Comparision between Unyvero and Conventional culture in the detection of different microrganisms 12/23/ Footer Text

96 Organism Unyvero Conventional Culture S.pneumoniae 13 1 Haemophius influenzae 6 2 S.aureus 4 0 Pseudomonas aeruginosa 6 4 Acinitobacter baumanii 7 5 Stenotrophomonas maltophilia 8 4 Klebsiella pneumoniae 6 1 E.coli 4 3 Maroxella catarallis 2 0 Proteus spp. 3 2 Enterobacter spp. 0 2 Pneumocyctis jerovesii 1 0 Pantonia 0 1 Legionella pneumoniae 4 0 Chamydia pneumoniae 1 0 Enterococcus spp. 0 2 Candida spp Not detected/ No growth /23/2013 Commensals Footer Text

97 TAT for Unyvero 4hrs For both ID and AST TAT for the conventional culture technique is hrs 12/23/2013 Footer Text 97

98 Comparison of the detection of antibiotic resistance between Unyvero System and the conventional Culture 12/23/ Footer Text

99 Organism No. Unyvero Conventional culture TAT 4 hrs Pseudomonas aeruginosa Klebsiella spp Acinitobacter baumanii Proteus spp E.coli /23/2013 Footer Text 99

100 Impact of Rapid diagnosis of Pneumonia on the management of pneumonia cases 12/23/ Footer Text

101 In 12 cases 6 VAP, 4 CAP, 2 HAP Empirical AB X modified either the same day or within 24 hrs according to Unyvero results for both ID and resistance markers With significant improvement after the modification 12/23/2013 Footer Text 101

102 4 patients all immunocompromised Legionella pneumophila detected and treated accordingly One Chlamydia pneumoniae detected in one cancer patient and treated accordingly 12/23/2013 Footer Text 102

103 Case 1 52 years Kidney transplant Case of CAP ( hospitalized) Unyvero in 4hrs: S.pneumoniae Hemophilus influenzae Empirical therapy: Respiratory quinolone No improvement Modification: Add ceftriaxone Marked improvement Conventional tculture After 48 hrs Haemophilus influenzae 12/23/2013 Footer Text 103

104 Case 2 57 years Kidney transplant A case of VAP Unyvero in 4 hrs: Acinitobacter baumanii Pseudomonas aeruginosa Resistance Markers: Int1, sul1 AND Oxa 51 Empirical therapy: Meropenem Conventional culture after 72 hrs Acinitobacter baumanii Resistant to meropenem Sensitive to colistin Modification upon resistance markers the same day: Add colistin 12/23/2013 Footer Text 104

105 Case 3 27 years patient in neurology ward A case of HAP Unyvero in 4 hrs: Conventional culture S.pneumoniae after 72 hrs Pseudomonas aeroginosa Proteus mirabilis Legionella pneumophila Pseudomonas Stenotrophomonas maltophilia aeruginosa S.aureus Sensitive strain Resistance markers: None Empirical therapy: Tazocin Modification of therapy Add respiratory quinolone for Legionella pneumophila 12/23/2013 Footer Text 105

106 Case 4 53 years patient in SB A case of lymphoma Unyvero in 4 hrs: Acinitobacter baumanii Stenotrophomonas maltophilia Pneumocystis jerovrci Resistance Markers: Oxa 51 CTX-M Tem Empirical therapy: Meropenem Modification: Add colistin Cotrimoxazole Conventional techniques After 72 hrs Acinitobacter baumanii only Sensitive to meropenem 12/23/2013 Footer Text 106

107 Acknowledgement

108 12/23/2013 Footer Text 108

109 Conclusion 12/23/ Footer Text

110 Management of Infectious Diseases 12/23/

111 In the era of antimicrobial resistance, are new antibiotics the solution??? 12/23/

112 Hit Hard Hit Appropriate Culture result Broad spectrum empirical antibiotics De-escalate 12/23/

113 Lab result after 2-5 days Proper laboratory diagnosis Treatment failure Lab Effective Results antimicrobial not matching agent with the empirical therapy Wrong ID Wrong Susceptibility Treatment success 12/23/

114 Less antimicrobial resistance Rapid Laboratory diagnosis Effective directed antimicrobial agent (difficult to grow, however clinical important Antimicrobial pathogens Stewardship and MDRO s) Treatment success 12/23/

115 Timing Line

116 Diagnosing Sepsis and Pneumonia Time waits for no body

117 Tomorrow is too late Thank You 12/23/ Footer Text